In 2012 the estimated incidence of salivary gland cancers (SGC) in the USA was 5-6% of the expected 40,250 head and neck cancers, representing an incidence of 0.9 per 100,000. Although rare overall, in the patient population affected, SGC is a devastating disease as most primary tumors return within 10 years and are uniformly fatal, and conventional chemotherapy provides transient, if any, benefit. In particular, the lack of models for preclinical drug testing and for exploration of the molecular events leading to SGC has crippled progress on this deadly disease. The primary goals of this study are to develop a preclinical platform of SGC, and to elucidate the molecular pathogenesis of SGC, with the overarching goal of providing a rationale for focused development of targeted treatments. To achieve the first goal, we will develop a human-in-mouse SGC xenograft platform. Implanting tumors in mice allows the generation of substantial amounts of tumor tissue that facilitates complex testing not possible in the small, original human sample. The tumors are maintained alive on mice to generate tissue for the characterization of molecular lesions in SGC, and to validate the xenografts as models that faithfully maintain the features in the originator tumor. We hope to develop an in vivo platform as close to the clinic as possible that will enable future drug development and biomarker discovery. To achieve the second goal we propose a detailed molecular characterization of primary tumors and xenografts, aided by Systems Biology integrative analyses. Our approach will combine static analysis of genetic events, and transcriptome and phosphoproteome analysis, with functional genetic screens using lentiviral based short-hairpin RNA (shRNA) libraries, to identify of genes and pathways essential for tumor survival. Together, this multi-level characterization will identify functional pathways for future therapeutic targeting, generate new hypotheses regarding the pathogenesis of salivary glands cancer, and promote the future development of in vivo models in which to test these hypotheses. )